TIME UNTIL THE START OF ANTIBIOTIC PROPHYLAXIS AND THE RISK OF OPEN FRACTURE INFECTION: A SYSTEMATIC REVIEW

ABSTRACT Open fractures are highly incident injuries closely related to the modern life, in which accidents caused by motor vehicles or other machines impart high energy to bone tissue. Individual morbidity is represented by the functional impairment resultant of infection, nonunion, or vicious healing. In terms of public health, there are huge costs involved with the treatment of these fractures, particularly with their complications. One of the critical issues in managing open fractures is the use of antibiotics (ATB), including decisions about which specific agents to administer, duration of use, and ideal timing of the first prophylactic dose. Although recent guidelines have recommended starting antibiotic prophylaxis as soon as possible, such a recommendation appears to stem from insufficient evidence. In light of this, we conducted a systematic review, including studies that addressed the impact of the time to first antibiotic and the risk of infectious outcomes. Fourteen studies were selected, of which only four found that the early initiation of treatment with antibiotics is able to prevent infection. All studies had important risks of bias. The results indicate that this question remains open, and further prospective and methodologically sound studies are necessary in order to guide practices and health policies related to this matter. Level of Evidence II; Therapeutic Studies Investigating the Results Level of Treatment.


INTRODUCTION
An open fracture is defined as a traumatic injury leading to exposure of a broken bone to external environment, with consequent contamination by microorganisms.There is always an associated soft tissue injury, the severity of which is directly related to the risks of complications, such as lack of consolidation and infection 1 The ever-increasing incidence of open fractures reflects developments in technology in the industry, military and transport fields.
Only in the US, it is estimated that up to 180.000 open fractures occur every year. 2 Industrial accidents, gunshot wounds and, mostly, motor vehicle accidents represent the main causes of open fractures, whose incidence approaches 30 cases per 100.000persons per year.[3][4][5] Open fractures inevitably lead to bacterial contamination of deep compartments, including subfascial soft tissues and bone.The subsequent risk of proliferation and infection is dependent on the interaction of variables such as the inoculum, host vulnerability and the lesion seriousness itself. 6 Current paradigms in management of open fractures have included completion of bony e soft tissue reconstruction in the first 48-72 hours.Inoculum size limitation has been achieved with modernization of initial fracture management, including lavage, debridement, fixation and antibiotic prophylaxis.The infectious complication worsens the prognosis, reduces probabilities that the fracture will consolidate, increases the risk of sequelae and dysfunction, including amputation and death.In the social realm, open fractures entail exorbitant costs with hospitalizations, surgical procedures, medication, physical therapy and rehabilitation, in addition to insurance and social security costs. 7-9 In this context, it is of great relevance to improve methods or strategies that provide a reduction in the incidence of infections associated with open fractures.Particular attention has been paid to the study of the relationship between early antibiotic (ATB) prophylaxis and the risk of infection.However, evidence is conflicting in this topic, mainly due to poor methodological quality of most studies published by now.This systematic review seeks to synthesize the body of evidence regarding this topic, in order to support relevant clinical decisions that may inform protocols and health policies addressing open fractures management.

Search strategy and information sources
We initially defined the review scope using PICO acronym 10,11

Inclusion and exclusion criteria
Randomized or non-randomized clinical trials, case-control and cohort studies were eligible, since they provided quantitative information on time to first ATB and infection endpoint.Data extracted was registered in a Microsoft Excel spreadsheet.Complementary items were antibiotic prophylaxis regimen and its duration, the time between the fracture and the first surgical debridement, what type of osteosynthesis was used, total length of hospital stay, at what point in the follow-up the outcome occurred, which bone was fractured, open fracture classification, general demographics, presence of clinical comorbidities and missing data information.Studies without intervention or outcome data were excluded.Regarding the design, we excluded case series, ecological studies and reviews.Others exclusions applied to duplicate, preclinical or studies with no full-text available.Only studies published in English were evaluated.

Evaluation criteria of selected studies
We used the ROBINS-I 13 tool for risk of bias assessment, which covers 7 essential domains (confusion, selection, missing data, classification of intervention, detection and selection bias, and bias due to deviation from the intended intervention).We chose to describe the results by separating the articles that provided recommendations from those that only indicated that early antibiotics were a current practice in trauma center.Whenever possible, we choose to group fractures with similar prognosis with the aim of improving external validity of the systematic review, since, in practice, it makes more sense to reach clinical decisions about antibiotic prophylaxis based on groups of fractures whose prognosis are similar.The main objectives of the synthesis were the identification of the methodological aspects, biases and measures of effect related to the binomial antibiotic precocity and infection.Ultimately, we meticulously investigated the selected studies, aiming at providing recommendations for practice and health policies in this matter.

RESULTS
Our search initially identified 604 titles, 71 from Pubmed, 271 from Embase, 117 from Google Scholar, 138 from Cochrane and 7 from Clinicaltrials.gov.Twenty duplicate studies were automatically removed by the reference organization tool (Endnote).Of the remaining 584, 527 were excluded for not containing minimal quantitative data on the intervention or outcome.We then proceeded to a detailed analysis of 57 titles, of which 15 duplicates were additionally excluded.Others exclusions applied to 22, due to ineligible designs, 6 due to full-text unavailability and 2 for other reasons.Another 2 studies were included by handsearch.In the end, 14 studies composed the present review.(Figure 1) Table 1.presents individual characteristics of the studies selected in the systematic review, with emphasis on results addressing the association between timing of first ATB and infectious outcome, including main author, year of publication, design, sample size, distribution of fractures by classification, risk of bias classification, information about time to first ATB and outcome.Table 2. contains information on the analytical methods used, results and whether the authors made recommendations on this topic.Finally, we summarize some comments on strengths and limitations of the selected studies.

DISCUSSION
Investigation of risk factors for infection in open fractures is extremely important, given the morbidity and health costs involved in treating such complications. 6,9At the individual level, deep infections are difficult to treat, often incurable, with tendency to become chronic and to permanently compromise the quality of life and the work performance.This is particularly relevant when considering that open fractures are especially incident in younger and economically active age groups. 3-5 Even with the optimization of techniques, devices and treatment protocols, infection rates can still reach 27% for type III fractures, even in specialized trauma centers. 14  In this context of high morbidity and functional impairment, a simple and inexpensive intervention able to avoid infectious complications becomes an attractive option to be tested.Still, contemporary literature does not give the intended answers, in the face of high heterogeneity and several methodological flaws of studies published by now.In our systematic review, we chose to list such limitations, or risk of bias, both in a descriptive way, as from a standardized tool, the ROBINS-I. 13 Bias risk assessment has shown has been especially useful in the internal comparison of studies included in the review.Generally, we observed a high risk of internal validity issues in the studies.In fact, of the 14 articles included in the systematic review, 6 were considered at serious risk of bias, 7 at critical risk and only 1 at moderate risk.The main problems encountered were substantial losses to follow-up, knowledge of the intervention at the time of assessing the outcome, and subjectivity in the classification of both the intervention and the outcome.
Regarding the follow-up, the main problems found were substantial losses, lack of definition or omission of measures of central tendency. 15,17,19,20,22,27In view of their designs, all studies allowed knowledge of the intervention at the time of evaluating the outcome.
In others, the way of measuring the outcome was not defined 25 , or it was subjective, 15,17,18,21,22,24,27 or without distinction between superficial and deep planes, 16 or even taken as a composite endpoint. 19 Another potentially serious question was the inconsistency in the way time to the first ATB was accounted for.In fact, some studies started time counting from the time of trauma, others from hospital admission, and still others from both timepoints, without performing a separate analysis for each of these situations.19,20,23 For example, patients whose first dose of ATB was administered after 30 minutes after admission and who became infected were mistakenly classified as early ATB takers, as the time elapsed between the trauma and hospital admission was not accounted for.So, eventual infections in this group are mistakenly associated with early ATB, when in fact should be attributed to late intervention.The net effect is a tendency to mitigate eventual contributions of early ATB in reducing the risk of infection.Some studies classified timing to first ATB from trauma time, 26 while others did so from hospital admission.15,24,25 The latter situation makes time registry of first ATB earlier than in fact it was.Some studies did not define the method of accounting time to first ATB.[15][16][17][18]21,22 We found situations of lack of balance between the comparison groups, with cases in which the vast majority of the sample either took ATB too early 18 or too late, 21,26 which tends to reduce statistical power and favor the null hypothesis.Few authors performed comprehensive control of confounders, 19,21,27,28 and most samples were not large enough to confer adequate statistical power, or, even if there was a representative sample, the number of outcomes was small, introducing a risk of false negative associations between confounders and the endpoint.Although there were substantial limitations in all studies, we found, in the most recent publications, better methodological and analytical elaboration, 19,21,[26][27][28] which reflects the growing interest in clarifying the real role of early antibiotic prophylaxis in the management of open fractures.Due to great heterogeneity, low methodological robustness and absence of randomized clinical trials on this topic, it was not possible to build a meta-analytic study, which could inadvertently compromise validity of results.However, the present review was valuable in identifying methodological gaps that can be optimized in future investigations.So, we suggest that upcoming studies carry out separate (or adjusted) analyzes to patients whose exact time of trauma is known and for those whose hospital admission is the starting time point to the first ATB.The time interval to the first ATB should be, in principle, analyzed as a continuous variable, avoiding artificial categorizations.Construction of ROC curves, from the mentioned time analysis, should be encouraged, and the data related to them, including sensitivity, specificity, AUC and respective confidence intervals, must be informed.The minimum follow-up of 3 months seems reasonable, since the vast majority of infections concentrate in this period.However, measures of central tendency and dispersion related to follow-up must be recorded in all cohorts.Those individuals lost at follow-up should be analyzed for the available data, especially the time interval to the first ATB.This is because the risk of bias due to missing data will be mitigated if the losses are balanced between patients who took early ATB and those who took it later.
Regarding the classification of outcome, we suggest that validated and objective methods are used, including, whenever possible, information on subfascial origin and microbiological results.Creative ways to prevent outcome assessors from knowing about the intervention or exposure (early or late ATB) should be implemented.All these measures tend to increase the methodological homogeneity necessary for the elaboration of future meta-analyses, something not currently feasible.Of the 14 studies included in our review, only 4 showed a positive correlation between the interval to the first ATB and the risk of infection.23,25,27 However, even though the benefits of early antibiotic prophylaxis in preventing infection are still to be confirmed, there are already centers that recommend or incorporate such practices, demonstrating that it is possible to implement antibiotic prophylaxis at a pre-hospital level.24,29 It is important to consider that even studies that show benefits with a small size of effect justify efforts to implement antibiotic prophylaxis as early as possible, because it is a safe, simple and cheap intervention, so that even if the number necessary to treat (NNT) is large, the cost-risk-benefit ratio will be highly favorable.Implementation of pre-hospital systemic antibiotic prophylaxis tends to be straightforward, as first-generation cephalosporins are acceptable options for all types of fractures in the Gustilo classification 23,[30][31][32] and do not produce considerable risks of severe allergic reactions.In fact, even in the rare cases of truly penicillin-allergic patients, the risk of cross-allergy is only 0.5% 33,34 Of the articles included in this systematic review, even the negative ones, there is a tendency to recommend early antibiotic prophylaxis or to indicate that such a practice is routine at the trauma center, which was the case in 8 of the 14 studies.Although the evidence is inconsistent, the biological plausibility, low costs and safety of the intervention are already sufficient arguments to justify implementation of early ATB in public health policies that deal with the pre-hospital management of open fractures.35

CONCLUSION
Our study synthesized the current evidence regarding the association between time to onset of antibiotic prophylaxis and the infectious outcome, reaching the conclusion that the benefits of early use of antibiotics in open fractures are yet to be confirmed, given the low methodological quality and potential risk of bias in the studies carried out so far.However, given the safety of the intervention, the ease of its implementation, its very low cost and its biological plausibility, we believe, at least at this point, that it is reasonable to keep the trend to organize services in order to institute pre-hospital administration of ATB, and that public health policies embrace this paradigm.Well-conducted prospective studies with blinding of outcome assessors and results analysts, and with adequate statistical power, can draw definitive conclusions about the potential benefits of early antibiotic prophylaxis in the management of open fractures.

AUTHORS' CONTRIBUTION:
Each author contributed individually and significantly to the development of this article.JM and AN: initial databases searches; review, selection and analysis of articles, paper writing and critical review of its intellectual content; approval of the final version of the manuscript to be published.
(Patient, Intervention, Comparison, Outcome), as follows: P: open fractures of any location and severity; I: early ATB after trauma; C: late ATB after trauma and O: superficial or deep infection.Search process followed PRISMA guidelines 12 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).An orthopedic surgeon and a microbiologist (JM and AN) independently searched the following databases: Cochrane, Embase, Pubmed, Google Scholar.Sources of gray literature were also searched, including ClinicalTrials.gov,WHO's International Clinical Trials Registry Platform (ICTRP), Networked Digital Library of Theses and Dissertations (NDLTD) and Dissertations and Theses Global.Disagreements were discussed and jointly solved.Search extended from June 2021 to February 2022, including the terms open fractures + infection + antibiotic + timing or time or early, with no date restriction.

SA:
bias due to confounding.B: selection bias.C: bias in classification of intervention.D: bias due to deviations from intended interventions.E: bias due to missing data.F: bias in measurement of outcomes.G: bias in selection of the reported result.L: low risk.M: moderate risk.S: serious risk.C: critical risk NI: no information.ATB: antibiotic.NC: not classified.NS: not specified.CDC: Centers for Disease Control.OR: Odds Ratio.ROC: Receiver Operator Characteristics.NHSN: National Healthcare Safety Network.Fx: fractures.Gt: Gustilo

Table 1 .
General characteristics of studies.

Table 2 .
Main results of studies included.
Intervention not known in 15% of patientsNo definite conclusion on the association of early ATB and infection, as most patients received late ATB Usual practice